tbuckley/cabot-search huggingface dataset:
Efficacy and safety of anlotinib in overall and disease-specific advanced gynecological cancer: A real-world study.
Authors: Xinyi Hong, Shanhu Qiu, Xia Wu, Sizhen Chen, Xiaoxiang Chen, Bei Zhang, Aiqin He, Ying Zhou, Yun Xu, Jianqing Wang, Yingchun Gao, Xizhong Xu, Li Sun, Yang Zhang, Libing Xiang, Jundong Zhou, Qun Guan, Bingwei Chen, Yang Shen
Journal: Journal of Clinical Oncology (2023)

5608 Background: Anlotinib is a novel oral small-molecule multi-target tyrosine kinase inhibitor that has been approved for treating non-small cell lung cancer. However, its efficacy and safety among patients with advanced gynecological cancer. We conducted this study to address this issue in the real-world setting. Methods: Data from patients treated with anlotinib for persistent, recurrent or metastatic gynecological cancer including cervical, endometrial, and ovarian cancer were collected from 17 centers from August 2018. The database lock-time was on March 2022. Anlotinib was administered orally on days 1–14 every 3 weeks until disease progression, severe toxicity occurred, or death. The outcomes included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 249 patients were analyzed, with a median follow-up of 14.46 months. The overall ORR and DCR were 28.1% (95% CI 22.6% to 34.1%), and 80.7% (95% CI 75.3% to 85.4%), respectively. Specifically, the ORR varied from 19.7% to 34.4% and the DCR differed from 81.7% to 90.0% in disease-specific advanced gynecological cancer. The median PFS was 6.1 months and ranged from 5.6 to 10.0 months in the overall and disease-specific advanced gynecological cancer, respectively. Larger cumulative dosage of anlotinib (&gt;700 mg) was in general associated with longer PFS in the overall and disease-specific advanced gynecological cancer. The most common adverse event related to anlotinib use was pain/arthralgia (18.3%). Conclusions: In conclusion, anlotinib holds promise in treating patients with advanced gynecological cancer, such as cervical, endometrial, and ovarian cancer, with reasonable efficacy and tolerable safety.
Tick tock on the stomach clock: Factors affecting time to diagnosis of gastric adenocarcinoma at an urban cancer center with a large East Asian patient population.
Authors: April Choi, Bhawneet Chadha, Hiten Doshi, Charly Edmiston, Anastasia Gurinovich, Jacob Matt Elkon
Journal: Journal of Clinical Oncology (2023)

e18508 Background: Gastric cancer is the fifth most common cancer in the world and disproportionately affects the East Asian population. Various factors contribute to this disparity such as genetics and environmental exposure. Given that language barriers can contribute to reduced quality of healthcare delivery, screening rates, and patient safety, it is important to assess the impact of language on the diagnosis of gastric cancer. Tufts Medical Center’s proximity to Boston’s Chinatown make our patient population unique for analysis of these factors. Here we present a single-institution experience of the factors affecting gastric adenocarcinoma time to diagnosis. Methods: We used ICD-10 codes to retrospectively identify patients at Tufts Medical Center with a diagnosis of gastric cancer between January 2011 and December 2021. We excluded patients that did not have a diagnosis of gastric adenocarcinoma or lacked adequate clinical documentation. We recorded demographic, clinical, and treatment characteristics including race (White, Asian, or other), primary language (English, Asian or other), presenting symptoms, enrollment in hospice, and interpreter status (certified, non-certified, none, or not applicable). Certified interpreters included professional medical services for in-person, video, or phone interpreters. Non-certified interpreters included family members, physicians fluent in the language, or others. We assessed the impact of these on the time between initial presentation to the healthcare system and eventual diagnosis of gastric cancer. Results: 80 patients were included in the analysis. Mean days to diagnosis by race were as follows: White (40), Asian (43), other (25), p = 0.20. Mean days to diagnosis based on language were as follows: English (40), Asian (43), other (6), p = 0.07. Mean days to diagnosis based on interpreter status were as follows: certified (19), non-certified (13), none (73), NA (40) (p = 0.05). When pairwise comparison was done, there was no difference between certified and non-certified interpreter (p = 0.40). There was no difference between certified interpreter and no interpreter (p = 0.06). There was a statistically significant difference between non-certified interpreter and no interpreter (p = 0.04). Presenting symptoms and eventual enrollment in hospice did not significantly impact time to diagnosis. Conclusions: We saw a shorter time from initial presentation to diagnosis of gastric adenocarcinoma in non-English speaking patients who used an interpreter at the initial visit compared to those who did not. One should always consider interpreter availability as an important part of reducing health disparities.
Development of a CCR8 monoclonal antibody to block CCR8 signaling and to abolish the immunosuppressive function of Treg for the treatment of cancers.
Authors: Guohuang Fan, JianFei Wang, Zhilong Wang, Yong Zhang, Yuanyuan Zhang, Binle Tian
Journal: Journal of Clinical Oncology (2023)

e14506 Background: The tumor microenvironment (TME) contains regulatory T (Treg) cells, which play a critical role in immunosuppression and are thus an attractive target for cancer therapy. The ideal approach would be to inhibit Tregs within tumors while sparing those in peripheral and normal tissues. Tumor-associated Tregs express the chemokine receptor CCR8, which is involved in the induction, expansion, migration, and immunosuppression of Tregs, making targeted inhibition of CCR8 signaling a potential therapeutic strategy against cancer. Methods: We have developed IPG0521, a monoclonal antibody antagonist of CCR8, and characterized its properties, including signaling blocking, chemotaxis, species cross-reactivity, anti-tumor efficacy, and synergistic antitumor effect with PD1 antibody. Single-cell RNA sequencing with CD45 + cells isolated from tumors treated with or without IPG0521 was also employed for profiling the mechanism of the antitumor effect of IPG0521 in the murine H22 cancer model. Results: IPG0521 inhibits receptor-mediated signaling and chemotaxis in Treg cells with a single-digit nanomolar IC50. It is cross-reactive in five species: mouse, rat, dog, monkey, and human. IPG0521 has shown excellent anti-tumor efficacy in several murine syngeneic cancer models, and its anti-tumor effect is enhanced when combined with a PD-1 antibody. Its sustained anti-tumor efficacy has been demonstrated in the murine H22 cancer model via even withdrawing the antibody during the study. The results of deep single-cell RNA sequencing on tumor-infiltrating lymphocytes (TILs) showed that the transcriptional profiles of these Treg cells could be distinguished into three distinct subsets based on molecular, functional, and immunosuppressive properties. These subsets were defined as the Treg_Foxp3 high subset, which exhibited low immunosuppression, the Treg_Foxp3 mild subset, which demonstrated mild immunosuppression, and the Treg_Foxp3 low subset, which had high proliferation. IPG0521 treatment resulted in a significant increase in the Treg_ Foxp3 high subset and a significant decrease in the Treg _ Foxp3 mild subset while no change in the Treg_ Foxp3 low subset, indicating a reduction in Treg immunosuppression. This change in Treg cells also altered the composition of other immune cells, including a significant increase in neutrophils and natural killer (NK) cells, which ultimately inhibited tumor growth. Conclusions: IPG0521 has potent anti-tumor effects in multiple tumor types, including lung, liver, and breast cancers, in both syngeneic and immune-humanized mouse models. It inhibits Tregs immunosuppression and activates CD8+ T cells to achieve its anti-tumor effects. These results support the development of IPG0521, which is currently under IND filing, as a novel therapeutic agent for the treatment of cancers.
A phase 1/2a, multicenter, open-label study of CNA3103 (LGR5-targeted, autologous CAR-T cells) in patients with metastatic colorectal cancer (mCRC).
Authors: Jayesh Desai, Jose Luis Iglesias, Lina T Jablonskis, Shaun McColl, Simon C Barry, Maria Pia Morelli
Journal: Journal of Clinical Oncology (2023)

TPS3632 Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker that is abundant in solid tumors, highly expressed in colorectal cancer and involved in tumor initiation, growth, and metastasis. Its expression is linked to poor survival and poor patient response to therapy in mCRC, and presents an attractive opportunity for selectively targeting a highly specific, functional CSC receptor in this disease. CNA3103 is a first-in-class cell product consisting of autologous T cells transduced to express a CAR to target LGR5. It contains the antigen-biding domain of BNC101, a humanized monoclonal LGR5 antibody previously tested in Phase 1 in mCRC subjects and demonstrated to be safe and well tolerated with no off-target binding activity. Methods: This is a first in human, multicenter, open label, Phase 1/2a dose escalation and expansion study to determine the safety of and overall best response to CNA3103 in subjects with mCRC. Up to 44 subjects (24 in Phase 1 and 20 in Phase 2a) will be enrolled. The trial follows a BOIN design with a minimum of 3 consecutively enrolled subjects per cohort, and a 28-day DLT evaluation period. Four cell dose levels (5 × 10 7 , 1.5 × 10 8 , 4.5 × 10 8 , 1.5 × 10 9 ) of CNA3103 will be evaluated. A Safety Monitoring Committee (SMC) will oversee the conduct of the study. The pharmacokinetic (PK) profile of CNA3103 in blood will be assessed. Exploratory objectives include evaluation of LGR5+ cells and CNA3103 in tumor biopsies, immune cellular profile, cytokine levels and circulating tumor DNA in blood, and immunogenicity of CNA3103. Main inclusion criteria: mCRC subjects positive for LGR5 expression and failing prior treatment with 5-FU, oxaliplatin and irinotecan-based regimens for metastatic disease; &gt;1 radiologically measurable lesion per RECISTv1.1; &gt;1 biopsiable lesion at baseline; ECOG 0 or 1; serum albumin &gt;3 g/dL; and normal organ and marrow function. Main exclusion criteria: BRAF-mutated disease, clinical ascites/ pleural effusions; active autoimmune/ connective tissue disease; history of inflammatory bowel disease or active peptic ulcer disease. The trial is sponsored by Carina Biotech. Phase 1 enrolment is limited to Australian sites. Phase 2a enrolment will take place in Australia and the US. For information, contact Lina Jablonskis lina@carinabiotech.com or +61 437 891 563.
Lisavanbulin in patients with recurrent glioblastoma: Phase 2a results and a consolidated analysis of response-predictive biomarkers.
Authors: Juanita Suzanne Lopez, Simon Haefliger, Ruth Plummer, Paul M. Clement, Heinz Philipp Laubli, Patrick Roth, T.R. Jeffry Evans, Lucy Brazil, Ghazaleh Tabatabai, Antje Wick, Wing Hing Hing Yau, Benjamin Wunderlich, Kirk Beebe, Joel Robert Eisner, Marc Engelhardt, Thomas Kaindl, Heidi A Lane, Peter Hau, Thomas Hundsberger, Joachim Steinbach
Journal: Journal of Clinical Oncology (2023)

2044 Background: Lisavanbulin (BAL101553, prodrug of BAL27862) destabilizes microtubules and promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic small molecule shown in rodents to penetrate the brain, with antitumor activity in orthotopic glioblastoma (GBM) models. In the Phase 1 part of this study 1 (NCT02490800), 2 of 5 patients with recurrent IDH-mutated G4 astrocytoma treated at active dose levels (15–30 mg/day) showed long-lasting objective responses and strong end-binding protein 1 (EB1) expression in GBM tissue by IHC. EB1 is a regulator protein on microtubules. Methods: The objective of the Phase 2 study was to investigate prospectively the response-predictive value of EB1, and to identify RNA-based response signatures in patients with recurrent GBM. A Simon’s two-stage design was used with an objective response rate (ORR) ≥ 2/9 required in Stage 1 to enable a final ORR ≥ 6/19. A prescreening program identified patients with EB1-positive archival GBM tissue. All patients received 25 mg oral lisavanbulin once daily. RNA-seq was performed on archival GBM tissues. Results: GBM tissue samples from 64 of 629 patients (10.2%) obtained from 13 sites in four countries were EB1-positive, and 18 of these patients received lisavanbulin. Of 9 patients with measurable disease evaluable for response in Stage 1, one patient had a partial response, and another had a 44% target lesion area reduction. Despite sustained activity in these patients, formal stage transition criteria were not met, and the study was closed. IHC testing for EB1 did not show sufficient enrichment for response, but it is thought that IDH status may play a role. In addition, RNA-seq analyses identified a five-gene signature that is distinct from expression patterns observed with EB1-IHC positivity, and predicts current responses irrespective of IDH status. This signature is characterized by homeobox gene downregulation, which may be implicated in the control of microtubule dynamics. Conclusions: This Phase 2a study supports previous study results that lisavanbulin is associated with durable responses and clinical benefit in a subset of patients with GBM. RNA-seq analyses of GBM samples suggest further evaluation of the lisavanbulin predictive response signature. 1 Lopez et al, JCO 2019;37,15 suppl, 2025. Clinical trial information: NCT02490800 . [Table: see text]
The impact of surgery on patients with VHL-associated tumors: An international patient survey.
Authors: Murali Sundaram, Christian Atkinson, Joshua Mann, Charley Cooper, Gavin Taylor-Stokes, Othon Iliopoulos
Journal: Journal of Clinical Oncology (2023)

4517 Background: Von Hippel-Lindau syndrome (VHL) is a rare hereditary neoplastic disorder caused by mutations in the VHL gene. Treatment (tx) options for patients are limited to multiple surgeries dispersed between regular scans, watchful waiting and txs that preserve organ function. Methods: An international, cross-sectional survey comprising patients in the United States (US), Canada (CA), the United Kingdom (UK), France (FR), and Germany (DE) was conducted. Patients were recruited via the VHL Alliance; data were collected between Dec 2021 and May 2022. For inclusion, patients must have renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNET), and/or central nervous system hemangioblastoma (CNS-Hb). Data collected included demographics, impact of most recent surgery on aspects of condition (1-7 scale 1 being greatly worsened and 7 being greatly improved), tx goals (top 3 goals from a list of 11), and patient preference in treatment. Patients were presented two scenarios “watch and wait” and potentially need surgery, or “take a once-daily pill” to delay a potential surgery. Results: 220 patients (68.2% female, median age 40.0, median disease duration 15.8 years) in the US (n=108), CA (n=37), the UK (n=21), FR (n=3), and DE (n=51) completed the study. 146 patients reported RCC (66.4%), n=122 reported pNET (55.5%), and n=190 reported CNS-Hb (86.4%). Among the top 4 symptoms experienced by patients were kidney cysts (n=82, 37.3%), numbness (n=59, 26.8%), dizziness (n=56, 25.5%), and fatigue/low energy (n=54, 24.5%). 205 (93.2%) patients had experienced surgery; n=171 (77.7%) had experienced multiple surgeries (median number of surgeries, 4.0). 166 patients recorded data on their most recent surgery. Of these, patients reported that their most recent surgery worsened (scored 1-3) their fatigue (51.8%), mental health (51.2%), and ability to go about daily life (45.2%). 47.3% of patients selected reduce the number of surgeries as a top tx goal, 46.4% selected being able to go about life as usual, 36.8% delay the need for surgery, and 33.2% improved quality of life. 73% of patients indicated they would prefer to take a pill which would possibly delay the time until surgery, rather than watch and wait to see if the tumor would grow. Conclusions: Surgery negatively impacts the lives of patients, leading to a worsening in their fatigue, mental health, and ability to go about daily life. Almost half of patients would like a treatment that reduces the number of surgeries, and over a third would like a treatment that delays the need for surgery. Nearly three quarters of patients would prefer to take a pill that might delay the need for surgery. Tx options that reduce the need for surgery would benefit this patient group.
Access to National Cancer Institute (NCI)–designated cancer centers among Native American patients with cancer.
Authors: Haoran Li, Kamal Kant Sahu, Georges Gebrael, Vinay Mathew Thomas, Nishita Tripathi, Nicolas Sayegh, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami
Journal: Journal of Clinical Oncology (2023)

e18646 Background: Native Americans (NA) have some of the highest mortality rates from cancer in the US. Despite that, they face significant geographic barriers to access to cancer care. However, little study addresses disparities in accessibility in NA population. This study aims to estimate the travel distance to National Cancer Institute (NCI)-designated cancer center for NA patients in Utah and the continental US. Methods: We first retrospectively collected geographic information of patients with genitourinary cancer (NA vs. white) from Feb 1, 2013, to Jan 31, 2023. The travel distance from patients’ home zip code to Huntsman Cancer Institute (HCI) at the University of Utah was calculated using GeoData ZIP Code Distance Calculations Matrix Template. Then, the shapefile was downloaded from the NCI website. Area Deprivation Index (ADI) state decile was used to match between NA reservations and the control block groups within the same state. The travel time was calculated using Google map. Locations were mapped in ArcGIS 10.7 using coordinates and a 5-digit zip code tabulation area (ZCTA). Results: During the ten-year period of time, a total of 468 NA patients were seen in our cancer clinic. The median travel distance for NA patients vs. white patients to HCI is 190.6 mi (range: 1.1-596.4 mi) vs. 21.6 mi (range: 1.1-269 mi, p&lt; 0.0001). In the continental US, the median travel distance from NA reservations vs. ADI-matched block groups to the nearest NCI-designated cancer centers is 186.5 mi (range 77.8-629 mi) vs. 159 miles (range 1.9-671.3 mi, p&lt; 0.01) (Table). Map data and travel time will be presented at the meeting. Conclusions: The travel distance to HCI for NA cancer patients in Utah was almost nine times longer than that of white cancer patients. It is also significantly longer from most NA reservations to the nearest NCI-designated cancer centers compared to ADI-matched block groups. This study highlights the significant disparity in cancer care accessibility faced by Native American communities and the urgent need for action to address this issue. [Table: see text]
An indirect comparison of elranatamab’s (ELRA) objective response rate (ORR) from MagnetisMM-3 (MM-3) vs real-world external control arms in triple-class refractory (TCR) multiple myeloma (MM).
Authors: Luciano J. Costa, Thomas William LeBlanc, Hans Tesch, Pieter Sonneveld, Ryan Kyle, Liliya Sinyavskaya, Patrick Hlavacek, Aster Meche, Jinma Ren, Alex Schepart, Didem Aydin, Marco DiBonaventura
Journal: Journal of Clinical Oncology (2023)

6618 Background: ELRA is a BCMAxCD3 bispecific antibody being investigated for the treatment of R/R MM. The phase 2 MM-3 trial was single-armed; the aim of this study (NCT05565391) was to contextualize the efficacy data from MM-3 with two real-world (RW) external control arms. Methods: A retrospective cohort study was conducted to indirectly compare the efficacy observed in MM-3 Cohort A (BCMA-naïve; N=123) from the 9-month data cut with two US-based oncology electronic health record databases, Flatiron Health (FH) and COTA, as external controls. MM-3 inclusion (eg, prior MM diagnosis, ECOG≤2, refractory to ≥1 PI, ≥1 IMiD, and ≥1 anti-CD38) and exclusion (I/E) criteria (eg, plasma cell leukemia, smoldering MM) were applied to each RW database to obtain comparable patient populations across sources. After imposing MM-3 I/E criteria, comparisons between data sources on ORR were conducted by estimating rate ratios (RRs) using log-binomial regression models (unweighted analysis). RRs were also estimated using both inverse probability treatment weighting (IPTW) and augmented IPTW (doubly robust) analyses to account for key covariates (eg, age, comorbidities, ECOG, ISS, prior lines/refractoriness, cytogenetic risk, extramedullary disease, lab values). Results: The 123 patients from MM-3 Cohort A were compared with the 152 and 233 patients identified from the FH and COTA databases, respectively. Treatment regimens in the RWD sources included various combinations of PIs, IMiDs, and mAbs, among other agents (eg, selinexor). Across unweighted, IPTW, and doubly robust analyses, the ORR for ELRA was significantly higher than treatments used for TCR MM patients from RWD sources (Table; all p&lt;.05). Conclusions: Among TCR MM patients who resemble those of the MM-3 trial, ELRA showed improved ORR compared with treatments currently used in clinical practice. [Table: see text]